Alessio Gambardella

Kaposi’s sarcoma: Etiology and pathogenesis, inducing factors, causal associations, and treatments: Facts and controversies

Abstract Kaposis sarcoma (KS), an angioproliferative disorder, has a viral etiology and a multifactorial pathogenesis hinged on an immune dysfunction. The disease is multifocal, with a course ranging from indolent, with only skin manifestations to fulminant, with extensive visceral involvement. In the current view, all forms of KS have a common etiology in human herpesvirus (HHV)-8 infection, and the differences among them are due to the involvement of various cofactors. In fact, HHV-8 infection can be considered a necessary but not sufficient condition for the development of KS, because further factors (genetic, immunologic, and environmental) are required. The role of cofactors can be attributed to their ability to interact with HHV-8, to affect the immune system, or to act as vasoactive agents. In this contribution, a survey of the current state of knowledge on many and various factors involved in KS pathogenesis is carried out, in particular by highlighting the facts and controversies about the role of some drugs (quinine analogues and angiotensin-converting enzyme inhibitors) in the onset of the disease. Based on these assessments, it is possible to hypothesize that the role of cofactors in KS pathogenesis can move toward an effect either favoring or inhibiting the onset of the disease, depending on the presence of other agents modulating the pathogenesis itself, such as genetic predisposition, environmental factors, drug intake, or lymph flow disorders. It is possible that the same agents may act as either stimulating or inhibiting cofactors according to the patient’s genetic background and variable interactions. Treatment guidelines for each form of KS are outlined, because a unique standard therapy for all of them cannot be considered due to KS heterogeneity. In most cases, therapeutic options, both local and systemic, should be tailored to the patient’s peculiar clinical conditions.

Wolf's post-herpetic isotopic response: Infections, tumors, and immune disorders arising on the site of healed herpetic infection

Herpes simplex viruses (HSV-1/HSV-2) and varicella-zoster virus (VZV) have several characteristics in common. Both are epidermoneurotropic, cause skin eruptions accompanied by sensory symptoms (itch, pain), damage peripheral sensory nerve fibers and cutaneous nerve endings, and interfere with neuromediator release, which can alter local mechanisms of immune control. For this reason, herpes-infected areas may become a preferential location for the subsequent onset of immunity-related skin disorders (infections, tumors, and dysimmune reactions), an event first reported by a neurologist and focused on by two brothers, a dermatologist and a pediatrician. The phenomenon therefore named Wolfs post-herpetic isotopic response (PHIR) refers to the occurrence of a new skin disorder at the site of a previous and already healed herpetic eruption (herpes zoster in most cases). Until now, we have been able to gather 189 well-documented cases of PHIR (all reported in the reference section), but our list is far from being complete. Some of the most emblematic cases are briefly described here. In some circumstances, the opposite of PHIR occurs, with diffuse skin disorders or eruptions that selectively spare herpes-infected areas (Wolfs post-herpetic isotopic nonresponse). Experimental investigations with patch testing have been performed in seven patients who were sensitized to nickel and had had herpes zoster in the past years. The tests were carried out bilaterally on the affected dermatomes and on the unaffected contralateral ones. The uneven immune responses we obtained have shown that the immune behavior of an herpes zoster-affected dermatome can be different from that of the corresponding contralateral dermatome, thus supporting the existence of immune dysregulation in herpes-infected areas.

Bullous pemphigoid initially localized around the surgical wound of an arthroprothesis for coxarthrosis

Holi dermatoses: annual spate of skin diseases following the spring festival in India. Indian J Dermatol 2009; 54: 240–242. 3 Ghosh SK, Bandyopadhyay D, Verma SB. Cultural practice and dermatology: the Holi dermatoses. Int J Dermatol 2012; 51: 1385–1387. 4 Ghosh SK, Bandyopadhyay D. Chemical leukoderma induced by colored strings. J Am Acad Dermatol 2009; 61: 909–910. 5 Ghosh SK, Bandyopadhyay D. Chemical leukoderma induced by herbal oils. J CutanMed Surg 2010; 14: 310–313. 6 Ghosh SK, Bandyopadhyay D. Concurrent allergic contact dermatitis of the index fingers and lips from toothpaste: report of three cases. J Cutan Med Surg 2011; 15: 356–357. 7 Ghosh SK, Bandyopadhyay D. Granuloma pyogenicum as a complication of decorative nose-piercing: report of eight cases from eastern India. J Cutan Med Surg 2012; 16: 197–200. 8 Saraswat A, Lahiri K, Chatterjee M, et al. Topical corticosteroid abuse on the face: a prospective, multicenter study of dermatology outpatients. Indian J Dermatol Venereol Leprol 2011; 77: 160–166.

Granulomatous dysimmune reactions (sarcoidosis, granuloma annulare, and others) on differently injured skin areas

Granulomatous disorders are chronic cell-mediated immune responses histologically characterized by collections of macrophages, epithelioid cells, and multinucleated giant cells. This disease spectrum often has an infectious origin, but sometimes neither an infective agent nor an inciting antigenic stimulus can be identified. The skin may be a preferential target for these disorders, especially in the areas that have been damaged by various forms of skin injury (eg, herpetic infections, trauma, thermal or solar burns, vaccinations, tattoos). These damaged skin sites frame the new concept of an immunocompromised cutaneous district (ICD), which defines a skin area with acquired immune dysregulation that can pave the way for the local onset of opportunistic disorders, such as infections, tumors, and granulomatous disorders. Sarcoidosis, granuloma annulare (GA), and forms of granulomatous vasculitis, such as Churg-Strauss syndrome (CSS) and Wegeners granulomatosis (WG), are the most common granulomatous disorders that occur in an ICD and may share common pathogenic mechanisms. Recent studies have found clinical and pathologic overlapping features across noninfectious granulomas. Although no unifying etiology exists, the development of granulomatous processes in the ICD has often been reported and the literature contains various hypotheses to explain it: (1) overactive immune response in a previously injured region with or without loss of immune tolerance; (2) overall reduced immune response; (3) retention of an exogeneous antigen or foreign body; (4) altered neural signaling; and (5) a combination of all the aforementioned processes. T helper cells, T regulatory cells, and macrophages, as well as a number of antigenic proteins, have been identified as potential contributing factors. In addition, a genetic predisposition and an intact systemic immune system are both instrumental for the persistence of local granuloma formation in the ICD.

Reactive angioendotheliomatosis following implantation of a knee metallic device: an instance of immunocompromised district

they are not appreciably stored within tissues. Rather, the particles’ small size enables them to be easily filtered by the kidneys without tubular resorption. Given normal renal function, indigo carmine is cleared from the circulation and seen in the bladder within 5–7 minutes. The side effects of indigo carmine dye are largely cardiovascular and most commonly involve hypertension and a reflex bradycardia with decreased stroke volume, leading to decreased cardiac output. Rarely, dysrhythmias, cardiac arrest, and anaphylaxis have also been reported. Uncommonly, indigo carmine dye can extravasate from the peripheral line into the skin and cause a dramatic but asymptomatic blue discoloration. The three prior instances of indigo carmine extravasation were also noticed upon the completion of surgery. As in the present case, the previously reported patients did not experience any symptoms and, other than the discoloration and edema of the affected arm, showed unremarkable findings on examination. In all cases, the discoloration resolved within 24–48 hours without any cutaneous or cardiovascular sequelae. Although indigo carmine dye extravasation into the skin is a benign, transient condition, its presentation is dramatic and can induce significant anxiety in both patients and clinicians who are unfamiliar with this complication. Dermatologists consulted for such rashes can reassure patients and the healthcare team that the discoloration will resolve completely without resultant tissue damage or permanent discoloration. Jacqueline N. Chu, BA Jozef Lazar, MD Joanna Badger, MD Department of Dermatology Stanford University School of Medicine Stanford CA, USA E-mail: jnchu@stanford.edu

Inverse notalgia paresthetica: a strange case of professional disease.

intermarriage. Fitzpatrick’s classification of skin types holds true today and can be used to broadly distinguish between skin types according to their ability or lack of it to burn and tan, and to distinguish among the degrees of lighter and darker skin, and thus seems more relevant than a geographically based descriptor such as Asian. The more accurate term South Asian skin as a descriptor for skin of Fitzpatrick phototypes IV–VI in people living in India has already been suggested and is factually correct not just for the 1.3 billion people of India but for populations of the entire Indian subcontinent, including those of Bangladesh, Pakistan, Sri Lanka, the Maldives, Afghanistan, Tibet, and Nepal. Interestingly, the Indian subcontinent is also referred to as the South Asian subcontinent by many workers for political considerations. Therefore, this letter may also serve as a reminder to use the term South Asian skin for skin of Fitzpatrick types IV, V, and VI in native people living in these locations.

Pemphigus vegetans of the folds (intertriginous areas)

Pemphigus vegetans (P Veg), the rarest form of pemphigus, is thought to be a variant of pemphigus vulgaris (PV). Classically, two subtypes of P Veg are recognized: (1) Neumann P Veg, which usually begins as PV with vesicles and bullae that rupture to form hypertrophic granulating erosions, then evolving into vegetating exuding masses; (2) Hallopeau P Veg, initially characterized by pustular lesions that, after rupturing, merge and gradually evolve into vegetating erosions with a centrifugal expansion. The disease typically affects the big folds (axillary, inframammary, inguinocrural, intergluteal), where semiocclusion, maceration, and mixed infections continuously incite exudation and granulation tissue formation (wet P Veg). In nonintertriginous locations, the vegetating buttons can dry out to change into warty, fissured, painful, seborrheic keratosis-like lesions (dry P Veg). Histologic examination indicates hyperplastic epidermis with intramalpighian leukocyte microabscesses and indistinct traits of suprabasal acantholysis. Immunofluorescence findings are similar to those of PV. Diagnosis is straightforward when PV lesions coexist. Difficulties can arise in cases with nonflexural location. Cytology (Tzanck test), histology, immunofluorescence, and ELISA search for anti-desmoglein antibodies are the diagnostic laboratory tools. Systemic treatment is similar to that for PV, high-dose steroids being the first choice therapy. Immunosuppressive agents and etretinate may allow a steroid-sparing effect. Topical treatment is aimed at countering the granulation tissue formation by means of several strategies (sublesional steroid injection, application of medicated gauzes in the involved flexures, chemical cautery or surgical excision of vegetating lesions).

Cutaneous sarcoidosis: an intriguing model of immune dysregulation

Sarcoidosis is a systemic granulomatous disease characterized by the presence of non‐caseating granulomas. Its etiology remains obscure. A plausible hypothesis suggests that a complex interplay of host factors, infectious processes, and non‐infectious environmental factors, matched with a susceptible genetic background, results in a pathway that leads to systemic granulomatous inflammation. Although presentations of sarcoidosis vary enormously, multi‐organ involvement is a common feature. Cutaneous involvement occurs in about 25% of patients with protean manifestations and variable prognoses. Skin manifestations are divided into specific lesions with histopathologically evident non‐caseating granulomas and nonspecific lesions arising from a reactive process that does not form granulomas. A peculiar form of cutaneous sarcoidosis is represented by sarcoidal lesions at sites of trauma that has caused scarring. The pathogenesis of scar sarcoidosis remains unknown. Scar sarcoidosis is also associated with herpes zoster infection, surgery, and tattooing. Such heterogeneous events, along with those at the sites of chronic lymphedema, thermal burns, radiation dermatitis, and vaccinations, occur on areas of vulnerable skin labeled “immunocompromised districts”. Numerous options are available for the treatment of cutaneous sarcoidosis. Although corticosteroids remain the treatment of choice for initial systemic therapy, other nonsteroidal agents have proven effective and therefore useful for long‐term management. Tumor necrosis factor‐α antagonists such as infliximab may have a role in the treatment of cutaneous sarcoidosis, especially in refractory cases that are resistant to standard regimens. Elucidation of the relationship of sarcoidal granulomas with malignancy and immunity may facilitate a better understanding of some pathomechanisms operating in neoplastic and immunity‐related disorders.

Performance of the “if in doubt, cut it out” rule for the management of nodular melanoma

Background The recognition of nodular melanoma is clinically challenging, and the diagnostic accuracy of dermoscopy and confocal microscopy is lower than for superficial spreading melanoma. Objectives To test a management strategy consisting in the excision of any nodular lesion that cannot be confidently and precisely classified as a benign tumor after clinical and dermoscopic examination. Methods Clinical and dermoscopic images of excised nodular lesions were retrospectively collected and evaluated. The evaluators were asked to record the level of diagnostic confidence for each lesion, by declaring if they were confident or doubtful about the given diagnosis. The NNE (number needed to excise) value was used to evaluate the efficacy of the proposed method. Results A total of 1,319 excised nodular lesions formed the study set. The NNE for any malignancy was 3.9 (634/164), while the NNE for melanoma was 13.2 (634/48). NNE for hypo and amelanotic melanoma was 27.3 (327/12). Conclusions Excising doubtful nodular lesions seems to be an effective management strategy not to miss nodular melanoma, resulting in an acceptable rate of unnecessary excision of benign lesions.

Seven non-melanoma features to rule out facial melanoma

Facial melanoma is difficult to diagnose and dermatoscopic features are often subtle. Dermatoscopic non-melanoma patterns may have a comparable diagnostic value. In this pilot study, facial lesions were collected retrospectively, resulting in a case set of 339 melanomas and 308 non-melanomas. Lesions were evaluated for the prevalence (> 50% of lesional surface) of 7 dermatoscopic non-melanoma features: scales, white follicles, erythema/reticular vessels, reticular and/or curved lines/fingerprints, structureless brown colour, sharp demarcation, and classic criteria of seborrhoeic keratosis. Melanomas had a lower number of non-melanoma patterns (p< 0.001). Scoring a lesion suspicious when no prevalent non-melanoma pattern is found resulted in a sensitivity of 88.5% and a specificity of 66.9% for the diagnosis of melanoma. Specificity was higher for solar lentigo (78.8%) and seborrhoeic keratosis (74.3%) and lower for actinic keratosis (61.4%) and lichenoid keratosis (25.6%). Evaluation of prevalent non-melanoma patterns can provide slightly lower sensitivity and higher specificity in detecting facial melanoma compared with already known malignant features.